Imidazolylmethylthioethyl alkynyl guanidines

ABSTRACT

Compounds of the formula    &lt;IMAGE&gt;  I  wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and nontoxic pharmaceutically acceptable acid addition salts thereof, are potent anti-ulcer agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our co-pendingapplication, Ser. No. 826,796, filed Aug. 22, 1977, now abandoned, whichin turn was a continuation-in-part of our application Ser. No. 803,009,filed June 3, 1977, and now abandoned.

SUMMARY OF THE INVENTION

This application relates to certainN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-alkynylguanidineswhich are H₂ receptor blocking agents, which inhibit gastric acidsecretion and which are useful in the treatment of ulcers.

BACKGROUND AND PRIOR ART

The clinical objective in treatment of peptic ulcer disease is todecrease gastric acid secretion, based on the principle "no acid, noulcer." Traditional peptic ulcer disease therapy involves control ofdiet and the use of antacids and anticholinergics.

There is evidence indicating that histamine may be the final commonpathway for stimulation of gastric secretion. This effect of histamineis mediated via H₂ receptors and is not inhibited by the classicalantihistamines, which are H₁ receptor blockers. A number of specific H₂receptor blocking agents (H₂ receptor antagonists) are now known. Thesecompounds inhibit basal acid secretion, as well as secretion by otherknown gastric acid stimulants, and are useful in the treatment of pepticulcers.

Burimamide (IIa) was the first clinically effective H₂ receptorantagonist. It inhibits gastric secretion in animals and man, but oralabsorption is poor. ##STR2## IIa; R² =H, Z=CH₂, X=S Burimamide B; R²=CH₃, Z=S, X=S Metiamide

c; R² =CH₃, Z=S, X=NCN Cimetidine

Metiamide (IIb), a subsequently evaluated H₂ antagonist, is more potentthan burimamide and is orally active in man. Clinical utility waslimited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc)is as effective an H₂ antagonist as metiamide, without producingagranulocytosis, and has recently been marketed as an anti-ulcer drug.The half-life of cimetidine is relatively short, thereby necessitating atherapeutic regimen of multi daily doses of 200 mg. tablets. There isthus a need for anti-ulcer agents which are longer acting and/or morepotent than cimetidine.

Reviews on the development of H₂ antagonists, including those discussedin the preceding paragraph, may be found in C. R. Ganellin, et al.,Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13(1976), and in references cited therein. Relevant patents are asfollows:

1. U.S. Pat. No. 3,950,333 discloses inhibitors of histamine-stimulatedgastric secretion having the formula ##STR3## wherein A, taken togetherwith the carbon atom, represents an unsaturated heterocyclic ringcontaining at least one nitrogen and may contain an additional heteroatom such as sulfur or oxygen, X₁ is inter alia (lower)alkyl, X₂ isinter alia hydrogen, k is 0 to 2, m is 2 or 3, provided that the sum ofk and m is 3 or 4, Y is oxygen, sulfur or NH, E is NR₂ in which R₂ ishydrogen, nitro or cyano, and R₁ is hydrogen, (lower)alkyl ordi(lower)alkylamino-(lower)alkyl.

2. Belgian Pat. No. 804,144 (Farmdoc 19437V) discloses inhibitors ofhistamine-stimulated gastric acid secretion having the formula ##STR4##in which HET is a 5 or 6 membered heterocyclic ring containing nitrogen,which may be substituted inter alia by alkyl, m and n are 0-4 and thesum of m and n is from 2 to 4, Z is sulfur, oxygen, NH or CH₂, and R₁ ishydrogen or (lower)alkyl.

3. Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors ofhistamine-stimulated gastric secretion having the formula ##STR5## inwhich HET is one of eight named heterocyclic rings (including imidazole)which may be substituted inter alia by (lower)alkyl, Z is sulfur or CH₂,X is S, CHNO₂, NCN or NH, Y is NH₂, (lower)alkylamino,di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl,trifluoroethyl or (CH₂)_(n) R in which n is 1-12 and R is OH,(lower)alkoxy, NH₂ or (lower)alkylamino; provided that, when X is NH, Yis trifluoroethyl or (CH₂)_(n) R; and when X is NCN, Y may not be aminoor (lower)alkyl.

This patent exemplifies and specifically claims the alkenyl compound ofthe formula ##STR6##

4. U.S. Pat. No. 3,894,151 discloses methods of inhibiting H₁ and H₂histamine receptors, and compositions containing an antihistamine plusan H₂ histamine receptor inhibitor, wherein the H₂ histamine inhibitoris selected from the following groups:

(a) Thioureas of the formula ##STR7## wherein A, taken together with thecarbon and nitrogen, is an unsaturated heterocyclic ring, X is interalia (lower)alkyl, n is 3-6, and R is hydrogen, (lower)alkyl, benzoyl oroptionally substituted phenylethyl.

(b) Compounds of the formula ##STR8## wherein A, taken together with thecarbon, is an unsaturated heterocyclic ring containing at least onenitrogen, X₁ is inter alia (lower)alkyl, X₂ is inter alia hydrogen, k is0 to 2 and m is 2-3, provided that the sum of k and m is 3 or 4, Y isoxygen, sulfur or NH, E is oxygen, sulfur or NR₂ in which R₂ ishydrogen, nitro or cyano, and R₁ is hydrogen, (lower)alkyl, benzoyl ordi(lower)alkylamino-(lower)alkyl.

(c) Amidine derivatives of the formula ##STR9## wherein A, takentogether with the carbon and nitrogen, is an unsaturated 5-6 memberedheterocyclic ring, X is inter alia (lower)alkyl, n is 2-5, R₁ is interalia (lower)alkyl; --NHR₃ or --SR₄, R₂ is inter alia alkyl containingfrom 1-4 carbons or, when R₁ is --NHR₃, cyano or nitro, R₃ is inter aliahydrogen, methyl or amino, R₄ is inter alia alkyl containing 1-6 carbonsor alkenyl or alkynyl containing 2-6 carbons.

(d) Isothioureas having the formula ##STR10## wherein A, taken togetherwith the carbon and nitrogen, is an unsaturated 5 or 6 memberedheterocyclic ring, X is hydrogen, halogen or benzyl, n is 2-4, R₁ ishydrogen or (lower)alkyl, R₂ is hydrogen, (lower)alkyl, amino or benzyl,or R₁ and R₂ taken together form an ethylene bridge.

(e) Amidines of the formula ##STR11## wherein n is 3 or 4.

The disclosures of U.S. Pat. Nos. 3,954,982 (a divisional of the above)and 4,000,302 (a continuation-in-part of the above) are substantiallythe same as that of U.S. Pat. No. 3,894,151.

5. Belgian Pat. No. 843,840 (Farmdoc 05613Y) discloses histamine H₂receptor antagonists having the formula ##STR12## wherein n is 2-3, Z issulfur or CH₂, Y is inter alia lower alkyl, and X is inter alia NCN.

Numerous other inhibitors of gastric acid secretion are known, but areconsidered much less relevant than those cited above because of stillgreater differences in structure from the instantly claimed compounds.The following patent covers compounds which are grossly different instructure from those claimed herein, but is cited as an example ofcompounds including alkynyl groups.

6. U.S. Pat. No. 3,897,555 discloses compounds of the formula ##STR13##wherein R₁ is one of 8 named heterocyclic rings (not includingimidazole), R₂ is inter alia hydrogen, (lower)alkyl), (lower)alkenyl orallyloxy, R₃ is an allyl or propargyl group which may be substituted bymethyl or ethyl groups, said R₃ having 3-6 carbon atoms.

COMPLETE DISCLOSURE

This invention relates to histamine H₂ receptor antagonists which areeffective inhibitors of gastric secretion in animals, including man,which are useful in the treatment of peptic ulcer disease, and whichhave the formula ##STR14## wherein R¹ is a straight or branched chainalkynyl group containing from 3 to 9 carbon atoms, inclusive, ornontoxic pharmaceutically acceptable acid addition salts thereof.

A preferred embodiment of the invention is a compound of the formula##STR15## wherein R⁴ is hydrogen or methyl, or a nontoxicpharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment of the invention is a compound of theformula ##STR16## wherein R⁴ is hydrogen or methyl and n is an integerof from 1 to 6, inclusive, or a nontoxic pharmaceutically acceptableacid addition salt thereof.

Another preferred embodiment of the invention is a compound of theformula ##STR17## wherein R⁴ is hydrogen or methyl, or a nontoxicpharmaceutically acceptable acid addition salt thereof.

A more preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable salt thereof.

Another more preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.

The most preferred embodiment of the invention isN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine or a nontoxic pharmaceutically acceptable acid addition saltthereof.

The compounds of the present invention may be prepared by severalreaction schemes, as illustrated below for a preferred compound.##STR18##

The reaction is conducted in a non-reactive solvent at a temperatureabove room temperature. As will be appreciated by those skilled in theart, R may be any substituent such that --SR will be a suitable leavinggroup. Thus, R may be (lower)alkyl, aryl, substituted aryl (e.g.p-nitrophenyl), aralkyl, --CH₂ CN, --CH₂ COOH, --CH₂ COOR', or the like.The N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-Risothiourea starting materials may be prepared by the proceduresdescribed in Belgian Pat. No. 804,144. The alkynylamine startingmaterials are either commercially available or may be prepared bymethods described in Bull. Soc. Chim. Fr., 490 (1958), Bull. Soc. Chim.Fr., 592 (1967) and Annales de Chimie (Paris), 3, 656 (1958). ##STR19##

The reaction is conducted in a non-reactive solvent at a temperatureabove room temperature. The substituent R may be as indicated in SchemeI, above. The 2-[(4-methyl-5-imidazolyl)methylthio]ethylamine startingmaterial may be prepared as described in U.S. Pat. No. 3,950,353. Thedisubstituted cyanodithioiminocarbonate which is used as a startingmaterial for the preparation of the N-cyano-N'-propargyl-SR isothiourea(see step a of Example 2) may itself be prepared by procedures describedin J. Org. Chem., 32, 1566 (1967) ##STR20##

Substituent P may be any of the suitable sulfhydryl protecting groupsknown in the art.

As used herein, the term nontoxic pharmaceutically acceptable acidaddition salt means the mono- or di-salt of a compound of this inventionwith a nontoxic pharmaceutically acceptable organic or inorganic acid.Such acids are well known and include hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric succinic,oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulfonic,acetic, propionic, tartaric, citric, camphorsulfonic, and the like. Thesalts are made by methods known in the art.

For therapeutic use, the pharmacologically active compounds of thisinvention will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in the basic form or in the form of a nontoxic pharmaceuticallyacceptable acid addition salt, in association with a pharmaceuticallyacceptable carrier.

The pharmaceutical compositions may be administered orally, parenterallyor by rectal suppository. A wide variety of pharmaceutical forms may beemployed. Thus, if a solid carrier is used, the preparation may betableted, placed in a hard gelatin capsule in powder or pellet form, orin the form of a troche or lozenge. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile solution for injection, or an aqueous or nonaqueousliquid suspension. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparation.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 to about 250 mg., and most preferably from about100 to about 200 mg.. The active ingredient will preferably beadministered in equal doses from two to four times a day. The dailydosage regimen will preferably be from 250 to about 1000 mg., and mostpreferably from about 500 to about 750 mg..

Histamine H₂ -receptor antagonists have been shown to be effectiveinhibitors of gastric secretion in animals and man, Brimblecombe et al.,J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H₂-receptor antagonist cimetidine has shown it to be an effectivetherapeutic agent in the treatment of peptic ulcer disease, Gray et al.,Lancet, 1 (8001), 4 (1977). The compound prepared in Examples 1 and 2below (hereinafter referred to as BL-5641) has been compared withcimetidine in various tests and has been shown to be more potent thancimetidine both as a histamine H₂ -receptor antagonist in isolatedguinea pig atria and as an inhibitor or gastric secretion in rats anddogs. Furthermore, the gastric secretion studies in dogs indicate thatBL-5641 has a longer duration of activity than cimetidine at equaldoses.

Histamine H₂ -Receptor Antagonism-Isolated Guinea Pig Atria Assay

Histamine produces concentration-related increases in the contractilerate of isolated, spontaneously beating guinea pig right atria. Black etal., Nature, 236, 385 (1972), described the receptors involved in thiseffect of histamine as histamine H₂ -receptors when they reported theproperties of burimamide, a competitive antagonist of these receptors.Subsequent investigations by Hughes and Coret, Proc. Soc. Exp. Biol.Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol. Exp. Ther.,200, 352 (1977) support the conclusion of Black and coworkers that thepositive chronotropic effect of histamine in isolated guinea pig rightatria is mediated via histamine H₂ -receptors. Black et al., Agents andActions, 3, 133 (1973) and Brimblecombe et al., Fed. Proc., 35, 1931(1976) have utilized isolated guinea pig right atria as a means forcomparing the activities of histamine H₂ -receptor antagonists. Thepresent comparative studies were carried out using a modification of theprocedure reported by Reinhardt et al., Agents and Actions, 4, 217(1974).

Male Hartley strain guinea pigs (350-450 gm.) were sacrificed by a blowon the head. The heart was excised and placed in a Petri dish ofoxygenated (95% O₂, 5% CO₂) modified Krebs solution (g./liter: NaCl 6.6,KCl 0.35, MgSO₄.7 H₂ O 0.295, KH₂ PO₄ 0.162, CaCl₂ 0.238, NaHCO₃ 2.1 anddextrose 2.09). The spontaneously beating right atrium was dissectedfree from other tissues and a silk thread (4-0) attached to each end.The atrium was suspended in a 20 ml. muscle chamber containingoxygenated modified Krebs solution maintained at 32° C. Atrialcontractions were recorded isometrically by means of a Grass FT 0.03force displacement transducer and recordings of contractile force andrate were made with a Beckman RP Dynograph.

A resting tension of 1 g. was applied to the atrium and it was allowedto equilibrate for 1 hour. At the end of the equilibration period asubmaximal concentration of histamine dihydrochloride (3 × 10⁻⁶ M) wasadded to the bath and washed out to prime the tissue. Histamine was thenadded to the bath in a cumulative fashion using 1/2 log 10 intervals togive final molar bath concentrations of 1 × 10⁻⁷ to 3 × 10⁻⁵. Thehistamine-induced increase in atrial rate was allowed to plateau beforethe next successive concentration was added. The maximal responseinvariably occurred at the 3 × 10⁻⁵ M concentration. The histamine waswashed out several times and the atrium allowed to return to controlrate. The test compound (1 × 10⁻⁵ M) was then added and after a 30minute incubation the histamine concentration-response was repeatedadding higher concentrations as needed.

The histamine ED50 values (concentration of histamine which increasedcontractile rate 50% of maximum) and 95% confidence limits before andafter the test compound were obtained by regression analysis asdescribed by Finney, Probit Analysis, 3rd ed., Cambridge (1971).Concentration-response curve displacement factors were calculated asfollows: ##EQU1## The factor obtained for BL-5641 was then expressed asa ratio of the factor obtained for cimetidine. ##EQU2##

The results obtained from these studies are summarized in Table 1.Cimetidine and BL-5641 displaced the histamine concentration-responsecurve to the right by a factor of 6.6 and 32.7, respectively. Based onthe concentration-response curve displacement factors, BL-5641 was about5.7 times more active than cimetidine as a histamine H₂ -receptorantagonist in isolated guinea pig right atria.

                                      Table 1                                     __________________________________________________________________________    Relative Activity of Cimetidine and BL-5641 in Isolated                       Guinea Pig Right Atria                                                                        Histamine ED50                                                                         Concentration-                                                       With 95% Response Curve                                                       Confidence                                                                             Displacement                                                                          Activity                                     Compound                                                                            N Concentration                                                                         Limits (μg/ml.)                                                                     Factor  Ratio                                        __________________________________________________________________________    Histamine        0.21                                                         Control                                                                             3         (0.18 - 0.25)                                                                          --      --                                                            1.39                                                         Cimetidine                                                                          3 1 × 10.sup.-5 M                                                                 (1.08 - 1.85)                                                                          6.6     1.0                                          Histamine        0.38                                                         Control                                                                             2         (0.27 - 0.53)                                                                          --      --                                                           12.44                                                         BL-5641                                                                             2 1 × 10.sup.-5 M                                                                 (7.81 - 20.28)                                                                         32.7    5.7                                          __________________________________________________________________________     N = number of experiments.                                               

Determination of Gastric Antisecretory Activity in the Two Hour PylorusLigated (Shay) Rat

The pyloric ligation procedure in the rat was designed by Shay et al.,Gastroenterology, 5, 53 (1945) for the study of perforating gastriculcers; however, as the method became known, it was also employed as ameans of studying rat gastric secretion, Shay et al., Gastroenterology,26, 906 (1954), Brodie, D. A., Am. J. Dig. Dis., 11, 231 (1966). Amodification of this procedure is presently used to evaluate compoundsfor gastric antisecretory activity.

Male Long Evans rats, 280-300 gm., are used. The animals are placed inindividual cages and fasted for 24 hours with free access to water.Under ether anesthesia, the stomach is reached through a midlineincision, and a cotton-thread ligature is placed around the pylorus.After wound closure, ether administration is stopped and either BL-5641,cimetidine or vehicle are administered intraperitoneally in a volume of1 mg./kg. BL-5641 and cimetidine are solubilized with one equivalent ofHCl and brought to the proper volume with water. The animals arereturned to their cages from which the water bottles have been removedand two hours later are sacrificed with ether. The stomach is removedand the 2 hour gastric collection is drained into a graduated test tubefor volume determination. Titratable acidity is measured by titrating aone ml. sample to pH 7.0 with 0.02N NaOH, using an Autoburet and anelectrometric pH meter (Radiometer). Titratable acid output iscalculated in microequivalents by multiplying the volume in millilitersby the acid concentration in milliequivalents per liter. The percentinhibition of acid output is calculated as follows ##EQU3##

The results obtained with BL-5641 and cimetidine are presented in Table2.

These results indicate that, in the two hour pylorus ligated ratpreparation, BL-5641 is at least as potent as cimetidine with respect tothe inhibition of gastric acid output.

                  Table 2                                                         ______________________________________                                        Effect of BL-5641 and Cimetidine                                              on Gastric Acid Output                                                        in the Two Hour Pylorus Ligated Rat                                           Dose (ip).sup.a    % Inhibition                                                                              ED50                                           Compound                                                                              μMole/kg.                                                                            mg./kg.  of Acid Output                                                                          μMole/kg.                             ______________________________________                                        BL-5641 40        11.1     80                                                         20        5.53     61        ˜11                                        10        2.76     37                                                 Dimetidine                                                                            40        10       66                                                         20         5       60        ˜14                                        10        2.5      40                                                          5        1.25     34                                                 ______________________________________                                         .sup.a At least 5 animals were employed at each dose.                    

Determination of Gastric Antisecretory Activity in the Gastric FistulaDog

Thomas type [Thomas, J. E., Proc. Soc. exp. Biol. Med., 46, 260 (1941)]stainless steel cannulae are inserted into the stomachs of beagle dogs(10-12 kg.) just orad to the pyloric gland area near the greatercurvature to provide a chronic gastric fistula. Animals are allowed torecover for at least two months before any testing is done. Dogs arefasted overnight (˜18 hours) with water ad lib prior to each experiment.The dogs are placed in a sling and an eight inch inside needle catheter(C. R. Baird, Inc.) with a 2 inch 17 gauge needle is inserted into a legvein fior purposes of drug administration. Gastric secretions arecollected every 15 minutes by gravity drainage from the opened cannula.Basal secretions are collected for two consecutive 15 minute periods andif these prove to be excessive (>4 ml./15 min.; pH <5.0) the animal isnot used. A modification of the procedure described by Grossman andKonturek, Gastroenterology, 66, 517 (1974) was followed. Immediatelyafter the second basal collection, histamine (100 μg./kg./hr.) isinfused for 90 minutes with a Harvard Infusion Pump in a volume of 6ml./hr. At this time either BL-5641, cimetidine (solubilized with oneequivalent of HCl and brought a proper volume with normal saline) ornormal saline is injected rapidly (within 30 seconds) in a volume of 0.1ml./kg. and then infusion of histamine continues for an additional 150minutes (total time of infusion is 4 hours). Each 15 minute sample ofgastric juice is measured to the nearest 0.5 ml. and titratable acidityagainst 0.02N NaOH (endpoint pH 7.0) is measured with an Autoburet andpH meter (radiometer). The percent inhibition of acid output iscalculated as described in the pylorus ligated rat procedure.

Equimolar doses of BL-5641 and cimetidine were administered to fivedifferent dogs and the results obtained are presented in Table 3.

Both BL-5641 and cimetidine produced an immediate inhibitory effect ongastric acid output. However, the degree of inhibition at equimolardoses was consistently greater and of longer duration with BL-5641 thanwith cimetidine. These results indicate that as an inhibitor ofhistamine-induced gastric acid output in the dog, BL-5641 is more potentand/or longer acting than cimetidine.

The invention is illustrated but in no way limited by the followingExamples.

                                      Table 3                                     __________________________________________________________________________    Effect of BL-5641 and Cimetidine on Gastric Acid                              Output in Conscious Gastric Fistula Dogs                                      Drug & Dose                                                                            Dog     % Inhibition Acid Output (N=1)                               (μM/kg. iv)                                                                         No. 15                                                                              30                                                                              45 60 75  90 105                                                                              120 min.                                     __________________________________________________________________________    BL-5641 (12)                                                                           24136                                                                             66                                                                              99                                                                              99 99 99  93 91 73                                           Cimetidine (12)                                                                        24136                                                                             63                                                                              99                                                                              89 76 54  48 41 14                                           BL-5641 (6)                                                                            22619                                                                             82                                                                              99                                                                              99 95 78  76 52 53                                           Cimetidine (6)                                                                         22619                                                                             84                                                                              96                                                                              73 67 65  54 40 32                                           BL-5641 (3)                                                                            23606                                                                             60                                                                              59                                                                              36 34 32  42 24  0                                           Cimetidine (3)                                                                         23606                                                                             43                                                                              27                                                                              15  0 17  38  8  0                                           BL-5641 (1.5)                                                                          24895                                                                             82                                                                              72                                                                              53 49 33   7  0  0                                           Cimetidine (1.5)                                                                       24895                                                                             73                                                                              57                                                                              60 29  0  18  0  0                                           BL-5641 (0.75)                                                                         23553                                                                             51                                                                              38                                                                              28 28 31  43 42 46                                           Cimetidine (0.75)                                                                      23553                                                                             50                                                                              10                                                                              24 17 35  27 25 19                                           __________________________________________________________________________

EXAMPLE 1N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine##STR21##

A mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (3.00 g, 0.0111 mole) and propargyl amine (2.50 g, 0.045mole) in acetonitrile (60 ml) was stirred at reflux for 65 hours, andthen was heated in a stainless steel pressure vessel at 120°-130° for 38hours. The reaction mixture was cooled, decanted from a tar, and thenevaporated to leave a gum (3.57 g). This material was placed on silicagel (100-200 mesh) and eluted with a mixture of methylene chloride (97parts) and methanol (3 parts). The product obtained from a middlefraction was crystallized by trituration under acetonitrile, and thenwas recrystallized from acetonitrile to yield the title compound (0.236g; 7.7%); m.p. 146°-149.5°.

Anal. Calc'd for C₁₂ H₁₆ N₆ S: C, 52.15; H, 5.83; N, 30.41. Found: C,51.86; H, 5.81; N, 30.70.

EXAMPLE 2N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-proparglyguanidine##STR22## a. N-Cyano-N'-propargyl-S-methyl isothiourea (A)

A solution of dimethyl cyanodithioiminocarbonate (16.00 g, 0.109 mole)and propargyl amine (6.03 g, 0.109 mole) in acetonitrile (320 ml) wasstirred at reflux for 4 hours, and then at 25° for 12 hours. Workup gavethe title compound A (13.58 g, 81%), m.p. 160°-164°.

b.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

A solution of A (11.71 g, 0.0765 mole) and2-[(4-methyl-5-imidazolyl)methylthio] ethylamine (13.10 g, 0.0765 mole)in methanol (250 ml) was heated at reflux for 64 hours. The solvent wasremoved by evaporation, the residue placed on silica gel (100-200 mesh)and chromatographed by gradient elution using methylenechloride/methanol; the latter fractions yielded 4.0 g of the titlecompound. Recrystallization from acetonitrile gave purified product m.p.150°-152.5° identical (ir, nmr, tlc) with the product prepared inExample 1.

EXAMPLE 3N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidine##STR23## a. N-(2-Butyn-1-yl)-N'-cyano-S-methylisothiourea (B)

A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole)and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) wasstirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. Themixture was cooled, then filtered to yield the title compound B, m.p.180°-183°.

b.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidine

A solution of B (6.82 g, 0.0407 mole) and2-[(4-methyl-5-imidazolyl)methylthio] ethylamine (6.98 g, 0.0407 mole)in methanol (140 ml) was heated at reflux for 40 hours. Workup andchromatography as described above for Example 2 yielded the titlecompound. When the title compound was prepared according to the generalprocedure of Example 1, it melted at 128°-130°.

EXAMPLE 4N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)guanidine

The general procedure of Example 1 is repeated except that the propargylamine utilized therein is replaced by an equimolar amount of3-butyn-1-amine, and the title product is thereby produced.

EXAMPLE 5N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidine

The general procedure of Example 1 is repeated except that the propargylamine utilized therein is replaced by an equimolar amount of4-pentyn-1-amine, and the title product is thereby produced; m.p.99°-103°.

EXAMPLE 6N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yl)guanidine

The general procedure of Example 3 is repeated except that the2-butyn-1-amine utilized therein is replaced by an equimolar amount of1,1-dimethylpropargylamine, and the title product is thereby produced.

EXAMPLE 7N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl)-N"-(3-butyn-2-yl)guanidine

The general procedure of Example 3 is repeated except that the2-butyn-1-amine utilized therein is replaced by an equimolar amount of1-methylpropargylamine, and the title product is thereby produced.

EXAMPLE 8N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidine

A mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea(3.00 g. 0.0111 mole) and 2-butyne-1-amine (3.07 g., 0.0445 mole) in 60ml. of propionitrile was stirred at reflux for 40 hours. TLC assay of analiquot of the reaction mixture showed a trace of the isothioureastarting material, so the mixture was refluxed for an additional 6 hoursand then stirred at room temperature for 64 hours. The solvent (alongwith excess amine) was removed at reduced pressure and the residual gumwas placed on silica gel (100-200 mesh) and eluted with a mixture ofmethylene chloride (97 parts) and methanol (3 parts). The middlefractions were combined and evaporated to give 1.81 g. of yellow gum.The gum was dissolved in 20 ml. of ethyl acetate and crystallized at-15° C. The resulting pale yellow solid (1.2 g.) was dissolved in 11 ml.of hot acetonitrile and recrystallized at -15° C; yield 1.072 g., m.p.128°-130° C.

Anal. Calc'd for C₁₃ H₁₈ N₆ S: C, 53.77; H, 6.25; N, 28.94; S, 11.08.Found: C, 53.72; H, 6.29; N, 29.62; S, 11.34.

EXAMPLE 9N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)guanidine

A mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea(3.00 g., 0.0111 mole) and 3-butyn-1-amine (3.13 g., 0.453 mole) in 60ml. of propionitrile was stirred at reflux for 40 hours. The solvent wasevaporated to give 5.40 g. of a syrup which was placed on 70 g. of100-200 mesh silica gel and chromatographed by gradient elution usingmethylene chloride/methanol.

    ______________________________________                                        Fraction                                                                              Eluant          Volume        Weight                                  ______________________________________                                         1      99 CH.sub.2 Cl.sub.2 /1 MeOH                                                                  100 ml.       --                                       2      "                70 ml.       --                                       3      "                50 ml.       0.117 g.                                 4      "                30 ml.       --                                       5      "                75 ml.       0.067 g.                                 6      "               150 ml.       0.080 g.                                 7      "               325 ml.       0.168 g.                                 8      98 CH.sub.2 Cl.sub.2 /2 MeOH                                                                   50 ml.       --                                       9      "               150 ml.       0.125 g.                                10      "               250 ml.       0.811 g.                                11      "               250 ml.       0.72 g.                                 12      97 CH.sub.2 Cl.sub.2 /3 MeOH                                                                  175 ml.       0.125 g.                                13      "               225 ml.       0.133 g.                                14      "               --            0.027 g.                                15      "               225 ml.                                                                                     0.002 g.                                16      "               200 ml.                                               17      95 CH.sub.2 Cl.sub.2 /5 MeOH                                                                  250 ml.       0.035 g.                                18      "               250 ml.       0.236 g.                                ______________________________________                                    

TLC (silica gel, 90 CH₂ Cl₂ /10 MeOH) indicated fractions 9-12 were pureand should be combined. Fractions 1-8 showed fast moving impurities.Fractions 13 and 14 showed some trailing impurities. Fractions 9-12 werecombined and evaporated to 1.72 g. of a yellow gum. The gum wasdissolved in 11 ml. of nitromethane and crystallized at -15° C (paleyellow solid, 1.18 g.), which was recrystallized from 9 ml. ofnitromethane to give 0.987 gm.; m.p. 86°-89° C (softens at 85° C).Infrared and NMR (100 MHZ) were clean and consistent with the desiredstructure. NMR showed that the product was solvated with approximately0.08 mole of nitromethane.

Anal. Calc'd for C₁₃ H₁₈ N₆ S.0.08 (CH₃ NO₂): C, 53.21; H, 6.22; N,28.84; S, 10.86.

Found: C, 52.68, 52.87; H, 6.28, 6.02, N, 29.39, 29.50; S, 11.22.

EXAMPLE 10N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidine

A mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea(3.00 g., 0.0111 mole) and 4-pentyn-1-amine (3.69 g., 0.0445 mole) in 60ml. of acetonitrile was stirred at reflux for 24 hours, and then allowedto stand at room temperature for 96 hours. The solvent and excess aminewere removed under reduced pressure and the residual yellow gum waspurified by chromatography on 50 g. of 100-200 mesh silica gel, usinggradient elution with methylene chloride/methanol (99:1-96:4). Themiddle fractions indicated by TLC to be pure were combined andevaporated to give 1.91 g. of yellow gum which was crystallized at -15°C from 18 ml. of ethyl acetate. The resulting white solid (1.25 g.) wasrecrystallized at -15° C from 10 ml. of acetonitrile to give 1.063 g. ofproduct; m.p. 99°-103° C.

Anal. Calc'd for C₁₄ H₂₀ N₆ S: C, 55.24; H, 6.52, N, 27.61; S, 10.53.Found: C, 55.43; H, 6.58, N, 28.26; S, 10.97.

We have recently found that, in the preparation ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidinevia Reaction Scheme I, selected reaction conditions in the last stepthereof give greatly improved yields of product as well as a productcontaining less impurities. The latter condition has the added advantageof permitting the initial ("crude") product to be isolated as acrystalline solid which may be more highly purified by simplerecrystallization, and avoids the chromatographic purification of theinitial crude product which we previously considered desirable whenusing other reaction conditions.

The selected reaction conditions referred to above consist of usingmethanol as solvent, utilizing a more concentrated solution in thereaction (approximately 1 gram of the substituted isothiourea per 5 mlof methanol), the use of a nitrogen sweep of the reaction apparatusduring the reaction, and the utilization of freshly distilledpropargylamine in the reaction.

Experiments have shown that the use of a nitrogen sweep during thereaction avoids the formation of small amounts of two as yetunidentified by-products which are formed in the absence of a nitrogensweep. These by-products, when present, resisted removal by columnchromatography and recrystallization. It is believed that the nitrogensweep prevents the formation of these by-products by removing the methylmercaptan gas as quickly as it is formed.

The increased yield ofN-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidineobtained by utilizing the above-described conditions is shown in thefollowing Examples but it is not intended that the invention be limitedin any way to their use.

EXAMPLE 11N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

The mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea(10.0 g; 0.0371 mole) and distilled propargylamine (20 ml; 0.325 mole)in methanol (50 ml) was stirred at reflux, under a positive pressurenitrogen atmosphere (nitrogen sweep), for 20.5 hours. The solvent andexcess amine were then removed by evaporation to leave a yellow-brownoil that readily crystallized. Trituration of the crude product underisopropanol (30 ml) gave the title compound as an off-white, friablesolid (8.11 g, 79%); m.p. 146°-148.5°.

EXAMPLE 12N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

A mixture ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea(100 g; 0.371 mole) and distilled propargylamine (150 ml; 2.44 moles) inmethanol (500 ml) was stirred at reflux under a positive pressurenitrogen atmosphere (nitrogen sweep) for 22 hours. The reaction mixturewas cooled, and the solvent and excess amine were removed by evaporationto leave an amber oil that readily crystallized. The crude product wastriturated under isopropanol (250 ml), cooled at 0° for 2 hours andcollected by filtration. The filter cake was washed with coldisopropanol and dried in vacuo over P₂ O₅ for 16 hours. The dried titleproduct was a near-white dense solid; yield 73.5 gm (71.7%) m.p.147°-149°.

EXAMPLE 13 Recrystallization ofN-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

The final products obtained in Examples 11 and 12 were combined (total81.3 g,) dissolved in hot isopropanol (1000 ml), filtered through"Super-Cel" and allowed to cool at room temperature for ca. 68 hours.The resulting crystalline product was recovered by filtration, washedwith cold isopropanol, pulverized and dried in a heated desiccator underhigh vacuum for ca. 45 hours. Yield 72.4 g (89% recovery); m.p.149°-151°. HPLC assay showed the purity to be ca. 99.5%. The NMR (100MHz) spectrum was clean and consistent.

Anal. Calc'd for C₁₂ H₁₆ N₆ S: C, 52.15; H, 5.83; N, 30.41; S, 11.60.Found: C, 52.42; H, 5.94; N, 30.51; S, 11.35.

We claim:
 1. A compound of the formula ##STR24## wherein R¹ is astraight or branched chain alkynyl group containing from 3 to 9 carbonatoms, inclusive, or a nontoxic pharmaceutically acceptable acidaddition salt thereof.
 2. A compound of the formula ##STR25## wherein R⁴is hydrogen or methyl, or a nontoxic pharmaceutically acceptable acidaddition salt thereof.
 3. A compound of the formula ##STR26## wherein R⁴is hydrogen or methyl and n is an integer of from 1 to 6, inclusive, ora noxtoxic pharmaceutically acceptable acid addition salt thereof.
 4. Acompound of the formula ##STR27## wherein R⁴ is hydrogen or methyl, or anontoxic pharmaceutically acceptable acid addition salt thereof. 5.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof. 6.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine.7. A nontoxic pharmaceutically acceptable salt ofN-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine.8.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof. 9.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable salt thereof. 10.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.11.N-Cyano-N-'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.12.N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl)guanidineor a nontoxic pharmaceutically acceptable acid addition salt thereof.